Session 2: Lipid Transport Flashcards

1
Q

Why is it a problem to transport lipids in the blood?

A

Because they are insoluble in water (hydrophobic).

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2
Q

How is this problem solved?

A

They are carried by lipoprotein particles (98%) or albumin (2%, mostly fatty acids).

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3
Q

What is the normal reference range of total cholesterol. How much of that are cholesterol esters?

A

Less than 5 mmol/L. Around 3.5 mmol/L would be cholesterol esters.

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4
Q

Phospholipids are classified. By what?

A

Their polar head groups.

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5
Q

What types of classes are there. Name 2.

A

Choline and inositol.

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6
Q

Where does the body get cholesterol from?

A

From diet but mainly from synthesis in the liver.

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7
Q

Why is cholesterol important?

A

They are needed for membranes as it regulates fluidity and rigidity.
They are precursors of steroid hormones such as cortisol, aldosterone, testosterone and oestrogen.
They are precursors of bile acids.

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8
Q

How is cholesterol generally transported around the body?

A

As cholesterol esters.

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9
Q

What is the difference between cholesterol and cholesterol ester?

A

Cholesterol ester has had a fatty acid tail added.

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10
Q

What are the main enzymes responsible used to turn cholesterol into cholesterol ester?

A

LCAT - lecithin cholesterol acyltransferase

Acyl-Coenzyme A cholesterol acyltransferase.

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11
Q

What are the 5 distinct classes of lipoproteins?

A
Chylomicrons
VLDL (very low density lipoproteins)
IDL (intermediate)
LDL (low)
HDL (high)
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12
Q

What are apolipoproteins?

A

They are proteins that are found on or in the plasma membrane of a lipoprotein. They make the lipoprotein water soluble as it has hydrophilic properties for the lymph or blood and hydrophobic properties for the lipid molecules of the lipoprotein.
Apolipoproteins are also important for their interaction with enzymes. They can be involved in activation oaf enzymes and in recognition of cell surface receptors.
The apolipoprotein composition of a lipoprotein particle determines the lipoproteins function in the body.

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13
Q

What do chylomicrons and VLDL mainly carry?

A

Fat

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14
Q

What do IDL, LDL and HDL mainly carry?

A

Cholesterol esters

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15
Q

In blood test how can you differ between the different lipoproteins?

A

By flotation ultracentrifugation. There will be bands of the specific lipoproteins as their density differ.

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16
Q

What are the six major classes of apolipoproteins?

A

A, B, C, D, E, H

Apolipoproteins can either be integral proteins or peripheral on the phospholipid bilayer.

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17
Q

What ALP can be found on HDL?

A

apoA1

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18
Q

What ALP can be found on VLDL, IDL, LDL?

A

apoB

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19
Q

What are ALPs functions?

A

Structural packing water insoluble lipids.
Co-factor for enzymes.
Ligands for cell surface receptors.

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20
Q

Outline chylomicron metabolism.

A

Chylomicrons get apoB-48 added to them before entering lymphatics.
Travels to thoracic duct -> left subclavian vein to blood.
Gets two new ALP: apoC and apoE.
apoC then binds to Lipoprotein lipase in the capillary walls of muscle and adipose. Here it releases fatty acids into the cells. This depletes the fat content of the chylomicron around 80%.
As the chylomicron has depleted to about 20% the apoC will dissociate and the chylomicron will become a chylomicron remnant as it returns to the blood.
LDL receptor on the hepatocytes binds to apoE, this causes the chylomicron remnant to be taken up by receptor mediated endocytosis. The remnant now returns to the liver and degraded by lysosomes.

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21
Q

Outline the VLDL metabolism.

A

Same as chylomicrons, however apoB100 is used instead. apoC and apoE added from HDL.

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22
Q

Outline metabolism of IDL and LDL.

A

VLDL -> IDL -> LDL this happens after the depletion of VLDL at the lipoprotein lipase.
As VLDL has interacted with LPL it depletes to around 30% and becomes an IDL. IDL can then be taken up by the liver, it can bind to LPL again to further deplete its TAG content. If it further depletes til around 10% the IDL will lose its apoC and apoE and becomes a LDL particle.

23
Q

What are LDL particles?

A

They are low density lipoproteins which contain a lot of cholesterol.

24
Q

What are the functions of LDL?

A

Provision of cholesterol from liver to peripheral tissue.

The peripheral cells have LDL receptors and take up LDL via process of receptor mediated endocytosis.

25
Q

What is the problem with LDL uptake?

A

LDL do not have apoC or apoE anymore so the liver can’t take it up efficiently. The liver’s LDL receptors have a high affinity for apoE.

26
Q

How is the problem with uptake of LDL clinically relevant? What are the consequences?

A

Due to it not being as readily cleared it has a higher half life than VLDL or IDL which means it is much more susceptible to oxidative damage. If LDL gets oxidised it will be taken up by macrophages and transform into foam cells. This contributes to the formation of atherosclerotic plaques.

27
Q

Explain how LDL enter cells.

A

apoB-100 works as a ligand to bind to LDL receptors. LDL is then taken up by the cell via endocytosis into endosomes. Lysosomes then digest the endosome and release cholesterol and fatty acids.

28
Q

How does HDL synthesis work?

A

Nascent HDL is synthesised the liver and intestine.
HDL particles can also come off from chylomicrons and VLDL when they are digested by LPL.
Free apoA1 can also require cholesterol and phospholipid from other lipoproteins and cell membranes to form nascent-like HDL.

29
Q

What is HDL maturation?

A

Nascent HDL will accumulate with phospholipids and cholesterol from cell linings and blood vessels.
They hollow core will progressively fill and the HDL will because of this take on a more globular shape.

Remember that transfer of lipids to HDL does not require enzyme activity.

30
Q

What is reverse cholesterol transport?

A

HDL can remove cholesterol from cholesterol-laden cells.

The cholesterol is then returned to the liver.

31
Q

Why is reverse cholesterol transport by HDL important?

A

Because it decreases the likelihood of foam cells forming in blood vessels and hence the formation of atherosclerotic plaques.

32
Q

What protein helps with the transfer of cholesterol to HDL?

A

ABCA1, cholesterol is then converted into cholesterol ester by LCAT.

33
Q

What are scavenger receptors?

A

Cells that require extra cholesterol can uses these receptors to obtain cholesterol from HDL.

34
Q

How can HDL exchange cholesterol ester for TAG with VLDL?

A

By the action of cholesterol exchange transfer protein also called CETP.

35
Q

Describe HDL metabolism.

A

Synthesis: liver and intestine usually. but also chylomicrons, VLDL or apoA1
Transport: Into bloodstream and starts to remove excess cholesterol from cells via ABCA1 and LCAT to form cholesterol ester. It can also exchange cholesterol for TAGs with VLDL. It can give cells that need cholesterol it via the cells scavenger receptors.
It is then taken up by steroidgenic cells to eventually form steroid hormones by receptor mediated endocytosis or by liver to eventually form bile salts.

36
Q

Function of chylomicrons.

A

Transport dietary TAGs from intestine to tissues such as adipose.

37
Q

Function of VLDL.

A

Transport of TAGs formed by liver to adipose for storage.

38
Q

Function of IDL.

A

Precursor of LDL. Transport of cholesterol formed by liver to tissues.

39
Q

Function of LDL.

A

Transport of cholesterol formed in liver to tissues.

40
Q

Function of HDL.

A

Transport excess cholesterol from tissue to liver or other cells to form bile salts in liver and steroid in other cells.

41
Q

What are hyperlipoproteinaemias?

A

When there is a raised level of one or more lipoprotein classes.

42
Q

How is this caused?

A

By either over-production or under-removal.

43
Q

Where is the general defect?

A

In enzymes, receptors or apoproteins.

44
Q

How many classes are there?

A

6

45
Q

What are the consequences of hyperlipoproteinaemias?

A

Some of them are associated with coronary artery disease. (Type 2a, Type 2b, Type 3, Type 4, Type 5.) The only one not associated with heart disease is Type 1.

Also if lipoproteins do not work correctly there can be an accumulation of fatty acids in the liver. This results in a fatty liver and can lead to liver failure.

46
Q

What is hypercholesterolaemia?

A

A high level of cholesterol in the blood.

47
Q

What are symptoms of hypercholesterolaemia?

A
Xanthelasma (yellow patches on eyelids)
Tendon Xanthoma (Nodules on tendon)
Corneal arcus (obvious white circle around eye. This is generally common in older people, however in young people it can be a sign of hypercholesterolaemia).
48
Q

Oxidised LDL is engulfed by macrophages and are then formed into foam cells. Where do the foam cells accumulate?

A

In the tunica intima of blood vessels. Here they form fatty streak.

49
Q

What is the consequence of atherosclerotic plaque.

A

Due to its growth in a blood vessel it will make the lumen more narrow. This can lead to angina (chest pain usually from not having enough blood flow to the heart muscle).

Also if the plaque ruptures it can trigger acute thrombosis which is a clot as platelets are activated and clotting cascade. This can cause MI or stroke.

50
Q

What is the first approach of treatment of hyperlipoproteinaemias?

A

Diet by reducing cholesterol and saturated lipids in diet. Also increase fibre intake. Fibre intake is good because it means bile salts are not being reabsorbed so more cholesterol is turned into bile salts.
Lifestyle by more exercise or stop smoking.

51
Q

What is the second approach of treatment of hyperlipoproteinaemias?

A

Statin as a drug. It reduces the cholesterol synthesis by inhibition of HMG-CoA reductase.
Bile salt sequestratants which bind bile salts in the GI tract and causes the liver to produce more bile salts using cholesterol.

52
Q

What are the ideal levels of the different cholesterols?

A

Total cholesterol - 5 mmol/L or less
Non HDL-cholesterol (total) - 4 mmol/L or less
LDL-cholesterol - 3 mmol/L or less
HDL-cholesterol - 1 mmol/L or preferably more. (1.2 in women)
Total cholesterol to HDL-cholesterol ratio - A ratio above 6 is considered high risk, the lower ratio the better.

53
Q

What is the preferred level of TAGs in blood?

A

Less than 2 mmol/L in fasted sample.